GNA13 loss in germinal center B cells leads to impaired apoptosis and promotes lymphoma in vivo

Jane A. Healy, Adrienne Nugent, Rachel E. Rempel, Andrea B. Moffitt, Nicholas S. Davis, Xiaoyu Jiang, Jennifer R. Shingleton, Jenny Zhang, Cassandra Love, Jyotishka Datta, Matthew E. McKinney, Tiffany J. Tzeng, Nina Wettschureck, Stefan Offermanns, Katelyn A. Walzer, Jen Tsan Chi, Suhail A K Rasheed, Patrick J. Casey, Izidore Lossos, Sandeep S. Dave

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

GNA13 is the most frequently mutated gene in germinal center (GC)-derived B-cell lymphomas, including nearly a quarter of Burkitt lymphoma and GC-derived diffuse large B-cell lymphoma. These mutations occur in a pattern consistent with loss of function. We have modeled the GNA13-deficient state exclusively in GC B cells by crossing the Gna13 conditional knockout mouse strain with the GC-specific AID-Cre transgenic strain. AID-Cre+ GNA13-deficient mice demonstrate disordered GC architecture and dark zone/light zone distribution in vivo, and demonstrate altered migration behavior, decreased levels of filamentous actin, and attenuated RhoA activity in vitro. We also found that GNA13-deficient mice have increased numbers of GC B cells that display impaired caspase-mediated cell death and increased frequency of somatic hypermutation in the immunoglobulin VH locus. Lastly, GNA13 deficiency, combined with conditional MYC transgene expression in mouse GC B cells, promotes lymphomagenesis. Thus, GNA13 loss is associated with GC B-cell persistence, in which impaired apoptosis and ongoing somatic hypermutation may lead to an increased risk of lymphoma development.

Original languageEnglish (US)
Pages (from-to)2723-2731
Number of pages9
JournalBlood
Volume127
Issue number22
DOIs
StatePublished - 2016

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Germinal Center
Lymphoma
B-Lymphocytes
Cells
Apoptosis
Immunoglobulin Somatic Hypermutation
Cell death
Caspases
Burkitt Lymphoma
Lymphoma, Large B-Cell, Diffuse
Immunoglobulins
Actins
B-Cell Lymphoma
Genes
Transgenes
Knockout Mice
Cell Death
Light
Mutation

ASJC Scopus subject areas

  • Immunology
  • Biochemistry
  • Hematology
  • Cell Biology

Cite this

Healy, J. A., Nugent, A., Rempel, R. E., Moffitt, A. B., Davis, N. S., Jiang, X., ... Dave, S. S. (2016). GNA13 loss in germinal center B cells leads to impaired apoptosis and promotes lymphoma in vivo. Blood, 127(22), 2723-2731. https://doi.org/10.1182/blood-2015-07-659938

GNA13 loss in germinal center B cells leads to impaired apoptosis and promotes lymphoma in vivo. / Healy, Jane A.; Nugent, Adrienne; Rempel, Rachel E.; Moffitt, Andrea B.; Davis, Nicholas S.; Jiang, Xiaoyu; Shingleton, Jennifer R.; Zhang, Jenny; Love, Cassandra; Datta, Jyotishka; McKinney, Matthew E.; Tzeng, Tiffany J.; Wettschureck, Nina; Offermanns, Stefan; Walzer, Katelyn A.; Chi, Jen Tsan; Rasheed, Suhail A K; Casey, Patrick J.; Lossos, Izidore; Dave, Sandeep S.

In: Blood, Vol. 127, No. 22, 2016, p. 2723-2731.

Research output: Contribution to journalArticle

Healy, JA, Nugent, A, Rempel, RE, Moffitt, AB, Davis, NS, Jiang, X, Shingleton, JR, Zhang, J, Love, C, Datta, J, McKinney, ME, Tzeng, TJ, Wettschureck, N, Offermanns, S, Walzer, KA, Chi, JT, Rasheed, SAK, Casey, PJ, Lossos, I & Dave, SS 2016, 'GNA13 loss in germinal center B cells leads to impaired apoptosis and promotes lymphoma in vivo', Blood, vol. 127, no. 22, pp. 2723-2731. https://doi.org/10.1182/blood-2015-07-659938
Healy, Jane A. ; Nugent, Adrienne ; Rempel, Rachel E. ; Moffitt, Andrea B. ; Davis, Nicholas S. ; Jiang, Xiaoyu ; Shingleton, Jennifer R. ; Zhang, Jenny ; Love, Cassandra ; Datta, Jyotishka ; McKinney, Matthew E. ; Tzeng, Tiffany J. ; Wettschureck, Nina ; Offermanns, Stefan ; Walzer, Katelyn A. ; Chi, Jen Tsan ; Rasheed, Suhail A K ; Casey, Patrick J. ; Lossos, Izidore ; Dave, Sandeep S. / GNA13 loss in germinal center B cells leads to impaired apoptosis and promotes lymphoma in vivo. In: Blood. 2016 ; Vol. 127, No. 22. pp. 2723-2731.
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abstract = "GNA13 is the most frequently mutated gene in germinal center (GC)-derived B-cell lymphomas, including nearly a quarter of Burkitt lymphoma and GC-derived diffuse large B-cell lymphoma. These mutations occur in a pattern consistent with loss of function. We have modeled the GNA13-deficient state exclusively in GC B cells by crossing the Gna13 conditional knockout mouse strain with the GC-specific AID-Cre transgenic strain. AID-Cre+ GNA13-deficient mice demonstrate disordered GC architecture and dark zone/light zone distribution in vivo, and demonstrate altered migration behavior, decreased levels of filamentous actin, and attenuated RhoA activity in vitro. We also found that GNA13-deficient mice have increased numbers of GC B cells that display impaired caspase-mediated cell death and increased frequency of somatic hypermutation in the immunoglobulin VH locus. Lastly, GNA13 deficiency, combined with conditional MYC transgene expression in mouse GC B cells, promotes lymphomagenesis. Thus, GNA13 loss is associated with GC B-cell persistence, in which impaired apoptosis and ongoing somatic hypermutation may lead to an increased risk of lymphoma development.",
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AU - Zhang, Jenny

AU - Love, Cassandra

AU - Datta, Jyotishka

AU - McKinney, Matthew E.

AU - Tzeng, Tiffany J.

AU - Wettschureck, Nina

AU - Offermanns, Stefan

AU - Walzer, Katelyn A.

AU - Chi, Jen Tsan

AU - Rasheed, Suhail A K

AU - Casey, Patrick J.

AU - Lossos, Izidore

AU - Dave, Sandeep S.

PY - 2016

Y1 - 2016

N2 - GNA13 is the most frequently mutated gene in germinal center (GC)-derived B-cell lymphomas, including nearly a quarter of Burkitt lymphoma and GC-derived diffuse large B-cell lymphoma. These mutations occur in a pattern consistent with loss of function. We have modeled the GNA13-deficient state exclusively in GC B cells by crossing the Gna13 conditional knockout mouse strain with the GC-specific AID-Cre transgenic strain. AID-Cre+ GNA13-deficient mice demonstrate disordered GC architecture and dark zone/light zone distribution in vivo, and demonstrate altered migration behavior, decreased levels of filamentous actin, and attenuated RhoA activity in vitro. We also found that GNA13-deficient mice have increased numbers of GC B cells that display impaired caspase-mediated cell death and increased frequency of somatic hypermutation in the immunoglobulin VH locus. Lastly, GNA13 deficiency, combined with conditional MYC transgene expression in mouse GC B cells, promotes lymphomagenesis. Thus, GNA13 loss is associated with GC B-cell persistence, in which impaired apoptosis and ongoing somatic hypermutation may lead to an increased risk of lymphoma development.

AB - GNA13 is the most frequently mutated gene in germinal center (GC)-derived B-cell lymphomas, including nearly a quarter of Burkitt lymphoma and GC-derived diffuse large B-cell lymphoma. These mutations occur in a pattern consistent with loss of function. We have modeled the GNA13-deficient state exclusively in GC B cells by crossing the Gna13 conditional knockout mouse strain with the GC-specific AID-Cre transgenic strain. AID-Cre+ GNA13-deficient mice demonstrate disordered GC architecture and dark zone/light zone distribution in vivo, and demonstrate altered migration behavior, decreased levels of filamentous actin, and attenuated RhoA activity in vitro. We also found that GNA13-deficient mice have increased numbers of GC B cells that display impaired caspase-mediated cell death and increased frequency of somatic hypermutation in the immunoglobulin VH locus. Lastly, GNA13 deficiency, combined with conditional MYC transgene expression in mouse GC B cells, promotes lymphomagenesis. Thus, GNA13 loss is associated with GC B-cell persistence, in which impaired apoptosis and ongoing somatic hypermutation may lead to an increased risk of lymphoma development.

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